Alzheimer's disease (AD) is a major public health problem, with neuropathological changes that may begin decades before clinical manifestation. Promising genetic and biological mechanisms are under investigation including lipid metabolism, inflammation, and glucose regulation. Another important proposed mechanism for increased AD risk is neuronal death through the lifelong cumulative effect of the body's response to stress. Systems such as the hypothalamic-pituitary-adrenal (HPA) axis effectively manage stress in the short term, however, there is long-term wear and tear on the body due to cumulative effects of stress reactivity and recovery, termed "allostatic load." A host of life stressors increases risk for depression, which, in turn, doubles risk for AD this is especially true for early-onset depression, which may be an indicator of maladaptive response to life stress. Psychosocial adversity such as early-life parental death and death of spouse or child, serious illness, disability or caregiving role in adulthood have been shown to increase risk for AD and cognitive decline in late life. However, few such studies exist, likely due to problems with recall bias inherent with retrospective reports of early life stressors. The present study will combine two tremendous resources to address this problem. The Cache County Study on Memory Health and Aging (CCS) has collected 12 years of prospective, detailed cognitive assessment with careful diagnosis of AD, and history of depression in a large population-based cohort of 5,092 persons aged 65 and older (90% participation rate). The Utah Population Database (UPDB) is a vast population-based genealogical, medical, and social database on individuals and multigenerational families. The UPDB will be used to objectively derive a set of lifespan stressors for members of the CCS cohort. These will be examined in relation to AD and cognitive decline in the CCS to address the following aims: 1) Evaluate whether psychosocial adversity in childhood adversely affects cognitive outcomes, and whether age at occurrence matters, 2) Evaluate whether psychosocial adversity in adulthood adversely affects cognitive outcomes, and whether childhood adversity places those with later adversity at enhanced risk, 3) Examine Early-onset Major Depression (EOD) and APOE for moderating effects on the association between life stressors and cognitive outcomes. A better understanding of which psychosocial stressors affect AD risk, and whether depression moderates these associations may help clinicians more selectively target AD prevention strategies to vulnerable individuals, decades before clinically identifiable symptoms might arise. PUBLIC HEALTH RELEVANCE: This study investigates the effect of lifespan stressors on Alzheimer's disease risk including interactions between childhood and adulthood stressors and between APOE genotype and stressors. Stressors will include experiences such as parental death in childhood, death of spouse or child in adulthood and disability, illness and caregiving in old age. Knowledge to be gained may help clinicians more selectively target AD prevention strategies to vulnerable individuals, decades before clinically identifiable symptoms might arise. [unreadable] [unreadable] [unreadable]